Holland et al. The Journal of Headache and Pain (2018) 19:20 The Journal of Headache https://doi.org/10.1186/s10194-018-0844-4 and Pain

REVIEWARTICLE Open Access PACAP in hypothalamic regulation of sleep and : importance for headache Philip R. Holland1*, Mads Barloese2* and Jan Fahrenkrug3

Abstract The interaction between sleep and primary headaches has gained considerable interest due to their strong, bidirectional, clinical relationship. Several primary headaches demonstrate either a circadian/circannual rhythmicity in attack onset or are directly associated with sleep itself. Migraine and cluster headache both show distinct attack patterns and while the underlying mechanisms of this circadian variation in attack onset remain to be fully explored, recent evidence points to clear physiological, anatomical and genetic points of convergence. The has emerged as a key area in several headache disorders including migraine and cluster headache. It is involved in homeostatic regulation, including pain processing and sleep regulation, enabling appropriate physiological responses to diverse stimuli. It is also a key integrator of circadian entrainment to light, in part regulated by pituitary adenylate cyclase-activating peptide (PACAP). With its established role in experimental headache research the peptide has been extensively studied in relation to headache in both humans and animals, however, there are only few studies investigating its effect on sleep in humans. Given its prominent role in circadian entrainment, established in preclinical research, and the ability of exogenous PACAP to trigger attacks experimentally, further research is very much warranted. The current review will focus on the role of the hypothalamus in the regulation of sleep-wake and circadian rhythms and provide suggestions for the future direction of such research, with a particular focus on PACAP. Keywords: Migraine, Cluster headache, Circadian, Circannual, Hypothalamus, Pituitary adenylate cyclase-activating peptide

Background disturbances [13, 14] and neuroimaging data suppor- Primary headache disorders represent a group of diverse ting abnormal hypothalamic activation in several pri- neurological attack forms that present with varying mary headache disorders [2, 4–6, 8, 15]thereisan intensity, duration, frequency and associated symptoms unmet need to develop novel mechanistic insight that [1]. Despite these underlying differences the hypothal- may herald novel therapeutic strategies. In particular pitu- amus has emerged as a critical component of several itary adenylate cyclase-activating peptide (PACAP) has attack forms, including migraine [2–5]andcluster emerged as a key neuropeptide involved in migraines and, headache [6–8].Thehypothalamusisakeyregulator as a parasympathetic and hypothalamic signaling of homeostatic mechanisms including sleep-wake molecule, that may be involved in cluster headache. cycles that are under circadian regulation [9]. Given PACAP is known to trigger migraine [16, 17]insuscep- the circadian and circannual nature of several attack tible individuals, plays a key role in hypothalamic circa- forms [10–12], the clinical association with sleep dian entrainment to light [18] and is the subject of significant interest as a potential therapeutic target for mi- * Correspondence: [email protected]; graine and cluster headache [19, 20]. As such, the current [email protected] review will focus on the potential regulation of sleep and 1Department of Basic and Clinical Neuroscience, Headache Group, Institute circadian mechanisms in primary headache disorders with of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK a particular focus on the regulation and future therapeutic 2Department of Clinical Physiology, Nuclear Medicine and PET, 70590 potential of modulating PACAP signaling. Rigshospitalet, Copenhagen, Denmark Full list of author information is available at the end of the article

© The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. Holland et al. The Journal of Headache and Pain (2018) 19:20 Page 2 of 8

Introduction regulated by at least two divergent mechanisms inclu- The ability to adapt to external environmental condi- ding circadian and homeostatic sleep pressure. This ele- tions is a fundamental principle for the survival of an gant regulatory mechanism allows the body to respond organism. As such several systems have evolved that per- to “sleep need” via the accumulation of an endogenous mit homeostatic regulation to internal and external cues, somnogens (e.g. Adenosine) on the background of a facilitating appropriate physiological responses. These circadian influence that entrains sleep-wake cycles to are most evident in the daily regulation of sleep-wake external cues such as seasonal light-dark patterns, for re- cycles with its circa 24-h rhythmicity (circadian), but view see [9]. The neuroanatomical basis for sleep was also include circannual (yearly), infradian (> day) and ul- initially postulated in response to a wave of “encephalitis tradian (< day, but > one hour) rhythms. Sleep itself is lethargica” with the neurologist Von Economo detailing generally dissected into wakefulness, non-rapid the presence of lesions in the border of the midbrain movement (NREM), and paradoxical or rapid eye move- and responsible for this excessive sleepi- ment (REM) sleep. Encephalographically, REM sleep and ness [23] and thus forming the basis for our current wakefulness are indistinguishable with fast, low ampli- understanding of arousal networks (see Fig. 1). tude, desynchronized oscillations, whereas NREM sleep Complimentary observations in patients presenting with stages I-III are characterized by increasingly lower fre- insomnia highlighted lesions within the lateral hypothal- quencies of synchronized cortical activity. The different amic area, with subsequent studies identifying specific stages of sleep are precisely regulated, complex mecha- cell groups including the ventrolateral nisms ensuring their consolidation at specific times (for (VLPO) that act to promote sleep [24] and inhibit review see [21]), timely progression and avoidance of arousal networks [25]. A further seismic step in our un- intermediary stages. derstanding of the regulation of sleep-wake cycles came While a complete understanding of the function of with the proposal of a “flip-flop” switch; whereby hypo- sleep remains to be fully characterized it clearly has a thalamic orexinergic synthesizing neurons act to restorative effect on the brain [22]. It is proposed to be reinforce the ascending arousal networks during

a b

c

Fig. 1 Mechanisms regulating sleep wake modulation. a. Orexinergic neurons originating in the (LH; Green) send excitatory projections to several brainstem nuclei that act to promote arousal. Ascending monoaminergic projections (purple) from the noradrenergic locus coeruleus (LC), glutamaterigic parabrachial (PB) and pedunculopontine (PPT), serotoninergic dorsal raphe (DR), dopaminergic ventral periaqueductal grey (vPAG), tuberomammillary nuceus (TMN) and GABAergic and cholinergic neurons in the basal (BF) diffusely innervate the cerebral cortex to promote arousal. There are also cholinergic projections (Blue) from the laterodorsal tegmental nuclei (LDT) and PPT nuclei that project to the to promote arousal. b. GABAergic ventrolateral preoptic (VLPO) neurons (Brown) act to inhibit the majority of the arousal nuclei, including LH orexinergic neurons to promote sleep. c. Homeostatic sleep pressure (Blue line) increases through wakefulness, likely via the accumulation of endogenous somnogens such as adenosine that excites VLPO neurons to promote sleep. This is combined with circadian sleep regulation (Red line) to create a balanced sleep wake cycle that is entrained to external environmental conditions. The circadian component is in part dependent on pituitary adenylate cyclase-activating peptide signalling within the hypothalamic as demonstrated by preclinical research Holland et al. The Journal of Headache and Pain (2018) 19:20 Page 3 of 8

wakefulness and are reciprocally inhibited in conjunction Sleep and circadian rhythms in headache with the ascending arousal nuclei by the VLPO during The interaction between sleep and headache has gained sleep [26]. The importance of these neurons in the considerable interest due to a strong but complex clin- regulation of arousal is evident in the devastating conse- ical relationship. This is evidenced from clinical and quences their loss has on patients suffering from narco- population studies demonstrating a high penetrance of lepsy [27]. sleep problems or manifest sleep disorders in headache Given the complex clinical relationship between circa- [44] and an ever increasing number of sophisticated dian/sleep regulation and headache, their shared physio- sleep studies [45–47] that point to several major points logical and neuroanatomical basis (see Fig. 1 and reviewed of physiological and neuroanatomical overlap (for review in [9, 28]), the emerging role for the hypothalamus in the see [9, 28]). regulation of migraine and cluster headache-relevant In agreement with a role for sleep disruption in homeostatic regulation (see [9, 28]) and the emergence of headaches cluster headache (CH) patients complain of pituitary adenylate cyclase-activating peptide (PACAP) as reduced sleep amount – that is complicated by the pres- a key neuropeptide in the regulation of migraine biology ence of consistent nocturnal attacks that may directly [20]. The current review will focus on the role of the disrupt sleep. However; CH patients demonstrate poor hypothalamus in the regulation of sleep-wake and circa- sleep quality both in- and outside of active cluster bouts dian rhythms, with a particular focus on PACAP. [10] highlighting a potential underlying disruption of sleep homeostatic regulatory mechanisms separate from PACAP the influence of the nocturnal attacks. This is further A detailed description of PACAP pharmacology is supported by a high prevalence of sleep apnea [46], con- discussed elsewhere in this special issue and in several founded by several overlapping risk factors – e.g. male recent reviews including [29]. Herein we provide a brief gender, high body mass index, smoking, and specific review for orientation purposes. PACAP is widely dis- sleep-linked attack forms, including hypnic headache [48]. tributed throughout the peripheral and central nervous The chronobiological nature of several headaches fur- system [30]. It occurs in two forms, PACAP-38 and ther highlights a key circadian/circannual component to PACAP-27 that are cleaved from the same preproPA- attack onset, whilst ultradian components have not been CAP protein. It is closely related to several neuropep- widely explored. The most prominent rhythmical head- tides including vasoactive intestinal peptide (VIP) and ache disorder is CH with its clear circadian [10–12] peptide histadine methionine. Interestingly, VIP induces (commonly during the early night) and circannual a similar headache [31] to PACAP [32] in healthy volun- periodicity - peak bout incidence potentially related to teers, but fails to induce a delayed migraine-like attack summer and winter solstice [49]. This is the time of year [31, 33]. PACAP and VIP share relatively equal affinity when the difference between night and day is greatest, for the VPAC1 and VPAC2 receptors, whereas PACAP and in a modern setting, perhaps places the greatest shows a greater affinity for the PAC1 receptor (for review stress on homeostatic entrainment mechanisms. There- see [34]). As such, despite sharing similar signalling fore, it could be postulated that a suboptimal function- mechanisms the PAC1 receptor has emerged as the first ing of the gain control in the light-governed entrainment PACAP receptor to be targeted clinically for migraines system could induce dysfunctional hypothalamic homeo- [19]. This is supported by preclinical evidence suggesting static mechanisms [3], leading in turn to increased at- that PACAP, but not VIP [35] sensitizes trigeminal neu- tack propensity. Migraine on the other hand is most rons, an effect that was blocked by PAC1 antagonism. commonly reported to initiate in the early hours of the In support of an emerging role for PACAP signalling morning [50] with evidence of a circannual periodicity in headaches PACAP-38 concentrations have been linked to the light season with fewer attacks during the shown to be elevated during migraine attacks [36, 37] dark season [51]. This would suggest that CH attacks and decreased interictally in episodic cluster headache, largely initiate during the early hours of sleep occurring with subsequent increases in bout [38]. With an in two common phases – associated with altered envi- increased genetic understanding of migraine and the ronmental light levels and migraine attacks largely initi- identification of multiple susceptibility loci [39], it is ate during the last hours of sleep/early in the arousal somewhat surprising that linkages to novel effective phase occurring most commonly in a single phase – as- pharmacological targets such as CGRP [40–42] or its re- sociated with higher environmental light levels. It has ceptor are not identified. As such it is less surprising been suggested that such nocturnal headache attacks are that there is no identified association between PACAP linked to specific macro-sleep phenomena [52]. While or PAC1 signalling in migraine. In comparison, a this has not been completely refuted, evidence is limited genome-wide association has been demonstrated for [45, 47] and recent research has suggested that noctur- PACAP in cluster headache [43]. nal attacks may be linked to the cycling between sleep Holland et al. The Journal of Headache and Pain (2018) 19:20 Page 4 of 8

stages, and not to a particular stage itself [10]. This Under normal conditions the rhythm of the SCN theory of heightened attack susceptibility during the is primarily influenced by light-dark cycles, with transitioning from one state to another may give light acting as the prominent “zeitgeber” in both di- important clues as to the potential mechanisms that urnal and nocturnal animals. While common photo- underlie attack initiation. For example, the presence receptors such as rods and cones are involved in of excessive yawning [53] during migraine premoni- light-entrainment non-image forming intrinsically tory symptoms points to a potential excess dopamin- photosensitive retinal ganglion cells (ipRGCs) that ergictone[54]; however, the subsequent transition to express encoded by the Opn4 gene play headache would be more likely associated with a a prominent role [65]. In general, direct projections decreased dopaminergic tone – as dopamine has been from light-responsive ipRGCs synapse on SCN neu- shown to be anti-nociceptive at least at the level of rons giving rise to the retinohypothalamic tract the trigeminocervical complex [55, 56]. (RHT), with additional sparse projections to other Traditionally, and due to technical limitations, enceph- hypothalamic nuclei. Additionally, indirect projec- alographic analysis of sleep has been limited to tions exist via the thalamic intergeniculate leaflet macrostrutural analysis of stage composition. However, that receives light-sensitive inputs and sends neuro- increasingly sophisticated analysis methods have peptide Y projections to the SCN. Early studies in revealed changes in the microstructure of sleep. Such rodents highlighted the presence of PACAP immu- analysis of sleep has revealed some interesting changes noreactivity in a subset of RHT retinal ganglion cells in headache patients including migraine and CH. that were responsive to light and projected to the Arousals are abrupt changes in EEG frequency of less SCN [66]. Later these PACAP containing neurons than 3 s duration. Such arousal phenomena are a part of were shown to express melanopsin and while normal sleep and an increasing number are seen with glutamate has been proposed as the main neuro- age. They indicate cortical activation and are generated transmitter in the RHT the role of PACAP is an by systems in the basal forebrain, thalamus, hypothal- interesting issue with respect to headache disorders. amus and brainstem via ascending projections. In a Peripherally administered PACAP is an established population especially prone to poor sleep quality one experimental tool for the induction of migraine [33]. would expect a high number of arousals, however, Both PACAP-38 and PACAP-27 potentially cross the counterintuitively, in both migraine and cluster blood brain barrier (BBB) in a saturable and non- headache a reduced number of arousals have been found saturable manner respectively [67, 68], although this [45, 57–59], suggesting that dysfunctional CNS neural is not supported by human studies [32]. The pineal networks including hypothalamic, thalamic and brain- gland lies outside the BBB and is innervated with stem nuclei may be a common feature. PACAP immunoreactive fibres that may in part arise from the trigeminal ganglion [69]. Within the but not the pituitary PACAP levels show a cir- PACAP in the regulation of sleep cadianexpression[70] that is phase dependent – As discussed above the ability to adapt to external with the highest levels occurring during the dark environmental conditions is a fundamental principle for phaseinrats.GiventhatPACAPcanstimulatemela- the survival of an organism. This allows for seasonal tonin synthesis [71, 72] and the lack of a functional variations in physiology and behavior that optimize our BBB, intravenous PACAP could, at least in theory, interactions with the local environment. Additionally, as modulate sleep-wake cycles via a direct action on the human intrinsic (“free-running”) circadian period is release. In agreement PACAP administra- 24.1 h [60] the ability to entrain the “master clock” in tion in rats increased the duration of REM sleep the hypothalamic suprachiasmatic nucleus (SCN) to [73]; however, PACAP-38 [74] administration in seasonal light-dark cycles ensures alignment to the healthy controls had no impact on the time spent in astronomical day. The SCN in turn acts as the central each sleep stage, but did modulate slow wave sleep. circadian regulator ensuring that peripheral oscillators The inconsistency between the current clinical and (“local clocks”) regulating local cellular rhythms are syn- preclinical data in response to PACAP administra- chronized in part via regulation of specific brain circuits tion is complex, given likely differences in BBB [61]. This includes the regulation of the autonomic penetrability and the known dose-dependent oppos- nervous system [62] that controls peripheral tissue and ing actions of PACAP on the SCN. the rhythmic release of hormones including melatonin from the pineal gland [63] that both entrains local PACAP in the SCN oscillators and inhibits SCN neuronal activity [64]ina Circadian phases are regulated at the level of the negative feedback manner. SCN by cell-autonomous, transcription translation Holland et al. The Journal of Headache and Pain (2018) 19:20 Page 5 of 8

feedback loops, whereby Period and Cryptochrome migraine with aura [89]. Importantly phosphorylation gene expression is inhibited by their respective pro- of PER proteins by CK1 proteins regulates the speed teins. The RHT sends light-sensitive projections to of the [90]. PER1 and PER2 are multiple regions of the SCN [75]thatsignalvia phosphorylated at multiple sites by CK1δ and CK1ε glutamate [76], aspartate [77]andPACAP[18], as that facilitates their degradation and subsequent re- well as indirect projections that utilize NPY [78]and lease of inhibitory repression of Clock/BMAL1 as GABA [79] as the key neurotransmitters (for review key elements of the cell-autonomous transcription see [61]). Electrical stimulation of the RHT releases translation feedback loops [91, 92]. Thus this loss of glutamate [80] that induces phase responses and function mutation that co-expresses altered circadian inhibition of glutamatergic signaling blocks SCN re- phases and migraine with aura indirectly highlight a sponses to light pulses [81] establishing glutamate as potential relationship between PER2 regulation and the prominent RHT – SCN neurotransmitter. While migraine. With respect to CH several studies have direct evidence for PACAP release in the SCN is explored potential relationships with clock gene vari- limited, local application of PACAP [66, 82]in-vitro ants due to the striking circadian and circannual was shown to phase advance SCN neurons during the periodicity of attacks. While no association has been subjective day via a PAC1 dependent mechanism, but not found between CH and per3 or the T-C Clock gene at night, suggesting a role for PACAP in daytime regula- polymorphism [93, 94] a recent publication deter- tion of the circadian cycle. During the subjective late night mined a potential association between the co-administration of PACAP and glutamate blocks the rs12649507 Clock gene polymorphism [95]thathas normal response to glutamate [83, 84], while inhibition of been previously associated with sleep duration [96]. PACAP signalling modulates this response, that was Patients with the rs12649507 AA genotype addition- supported by the ability of PACAP to potentiate glutamate ally demonstrated increased Clock gene expression, induced light responses in-vivo [83]. Conversely, during raising the possibility that CH may result from circa- the early night PACAP potentiated glutamate induced dian misalignment. phase delays that was inhibited by blocking PACAP The effects of administration of PACAP on sleep in signalling [83]. As such PACAP may act to provide a gain humans has not been extensively studied and the control mechanism for glutamate induced phase shifts PACAP-effects observed in animals (increase in REM- that could have a significant determinant on multiple sleep) [97] have so far not been reproduced in downstream peripheral oscillators [85]. This role of humans under the described conditions. This does PACAP is further supported by the use of available not exclude an effect in humans however as there are PACAP or PAC1 knock-out mice that maintain a stable many variables that could be changed. As noted pre- activity-rest pattern during constant darkness and demon- viously, a recent study has implicated a common vari- strate stable expression of clock genes. Despite this ant of the PACAP receptor gene (ADCYAP1R1) [43] apparently normal circadian phenotype PAC1 deficient in CH but the results were not replicated in a larger mice demonstrate impaired photic entrainment in agree- study [98]. Further, the specifics of how systemically ment with the above pharmacological data [86, 87]and administered PACAP could regulate circadian rhythms disrupted circadian food anticipatory behaviours [88]. remains to be elucidated. The proposed mechanism of PACAP and glutamate induced phase alterations is via the light sensitive clock genes, Period 1 (per1)andPeriod 2 (per2)[84]. Conclusion Ex-vivo glutamate administration on SCN brain PACAP is emerging as an important molecular target slices induces robust increases in per1 and per2 ex- in the pathophysiology of primary headache disorders, pressions; however, micromolar concentrations of with a particular focus on migraine and CH. It is well PACAP alone was unable to modulate their expres- established that there is a clear clinical association sion. In agreement with a role for PACAP as a between these conditions and sleep disturbances; modulator, pre-administration of micromolar concen- while preclinical studies are beginning to propose trations of PACAP completely blocked the effect of novel mechanisms that underlie these shared etiolo- glutamate, whilst nanomolar concentrations induced gies [9, 89]. It is clear that migraine [50]andCH per1 and per2 expression [84].Whiledataonthe [10–12] have a clear rhythmicity, both at the circa- role of specific clock genes in headache are limited dian and circannual level and as such future research the recent discovery of human mutation in the cata- should explore both the underlying mechanisms of lytic domain of the gene encoding casein kinase 1δ this association and the potential for novel transla- (CK1δ;CK1δ-T44A) that was associated with both tional lifestyle and pharmacological targets to lighten familial advanced sleep phase syndrome (FASPS) and the burden of disease. Holland et al. The Journal of Headache and Pain (2018) 19:20 Page 6 of 8

There is a need to develop a greater understanding of Received: 10 November 2017 Accepted: 12 February 2018 the rhythmic changes observed in headaches. For ex- ample, while PACAP and other molecules such as CGRP and nitroglycerin can be potent migraine triggers, little is References 1. S. Headache Classification Committee of the International Headache (2013) known about circadian and circannual variability in their the international classification of headache disorders, 3rd edition (beta response. Experimentally, individual aspects of circadian version). Cephalalgia 33:629–808 variation in trigeminovascular nociceptive processing, 2. Denuelle M, Fabre N, Payoux P, Chollet F, Geraud G (2007) Hypothalamic activation in spontaneous migraine attacks. Headache 47:1418–1426 sleep and autonomic regulation may be studied but it is 3. Holland PR (2017) Biology of neuropeptides: Orexinergic involvement in ultimately in the combination of our knowledge of these primary headache disorders. 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Sherin JE, Shiromani PJ, McCarley RW, Saper CB (1996) Activation of Springer Nature remains neutral with regard to jurisdictional claims in ventrolateral preoptic neurons during sleep. Science 271:216–219 published maps and institutional affiliations. 25. Szymusiak R, McGinty D (2008) Hypothalamic regulation of sleep and arousal. Ann N Y Acad Sci 1129:275–286 Author details 26. Saper CB, Scammell TE, Lu J (2005) Hypothalamic regulation of sleep and 1Department of Basic and Clinical Neuroscience, Headache Group, Institute circadian rhythms. Nature 437:1257–1263 of Psychiatry, Psychology and Neuroscience, King’s College London, London, 27. 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